Addictive drugs usurp the brain's intrinsic mechanism for reward, leading to compulsive and destructive behaviors. While there have been significant advances in understanding the neurochemical and physiological changes in addiction, clinically effective treatments have eluded researchers. Remarkably, there are no FDA approved drugs for treating psychostimulant abuse. In the ventral tegmental area (VTA), the center of the brain's reward center, GABAergic inhibition controls the excitability of neurons. A primary component of the GABAergic inhibitory pathway is formed by GABAbeta receptors that couple to G protein-gated potassium (GIRK) channels. Studies show that an acute injection of psychostimulant in mice produces a robust depression of the GABAbeta receptor GIRK inhibitory pathway in VTA GABA neurons but not in DA neurons. This drug-evoked depression of GABAbetaR signaling in GABA neurons removes an intrinsic brake on GABA neuron firing that would result in enhanced GABA-mediated inhibition of DA neurons and potentially reducing reward perception. This acute effect of psychostimulants provides a unique opportunity learn how to control the VTA output through alterations in the levels of endogenously expressed GABAbeta-GIRK proteins in VTA GABA neurons. However, detailed pre-clinical studies are needed to better understand how adaptations in GABAbetaR-GIRK signaling in VTA GABA neurons affect the output of the VTA and motivated behavior. The main objectives of this project are to determine the role of phosphorylation of the receptor in this change of GABAbeta-GIRK signaling and assess whether down-regulation of GABAbeta receptor alters the addictive properties of psychostimulants. Specifically, we will (i) test the hypothesis that dephosphorylation of the receptor underlies the ability of psychostimulants to down regulate GABAbeta receptor activity in VTA GABA neurons, (ii) elucidate the structural and molecular interactions governing protein phosphatase 2A (PP2A) association with the GABAbeta receptor, and (iii) determine impact of GABAbeta-GIRK signaling in GABA neurons on VTA function and motivated behavior. The research team will use a comprehensive approach that combines molecular genetics, structural biology, biochemistry, physiology and behavior. The hypothesis that psychostimulants regulate synaptic inhibition by modulating GABAbeta receptor phosphorylation, a process that is dependent upon a fraction of PP2A directly associating with the receptor, is an innovative and untested model. The concept that the C terminal domain of the GABAbeta receptor serves as the epicenter for coordinating regulatory proteins for receptor function could provide the framework for understanding the molecular regulation of other GPCRs in the brain. Baclofen (Lioresal) is an agonist of the GABAbeta receptor and is being evaluated for treating alcoholism, addiction and autism. Selectively targeting the GABAergic inhibitory system as described here could lead to improved clinical use of baclofen and perhaps to new drugs for treating addiction and other neurological disorders.